Recent technological advances in genomics, including the sequencing of the genome in humans and several laboratory model species, provide valuable information on similarities in the number and organization of genes among species. An important finding is that many developmental components and processes involved in organization of the body plan are shared across phyla. In particular, the homeobox (HOX) genes are important in developmental patterning, and are involved in establishing cell identities along the anterior-posterior axis of all higher metazoans. Because HOX genes are conserved across phyla and have been well described in the fruitfly, roundworm, zebra fish and the mouse, it is possible to identify related human sequences. Sequence variations in human fetal HOX genes have yet to be systematically evaluated for their relationship to human fetal survival and developmental defects. The goals of the proposed research are to establish a bank of human fetal tissues and to evaluate selected HOX genes known to control morphogenesis in laboratory models. Chorionic villus samples can be collected as early as 10 to 12 weeks and amniotic fluid samples at 16 to 20 weeks of human pregnancy. When collected in a clinical setting, these samples can be linked to pregnancy outcome through ultrasound findings and results of routine obstetrical care. A data base can be developed to catalog the spectrum and allelic frequencies of polymorphisms in HOX genes during normal development, and to determine whether sequence variations are associated with fetal lethality and/or dysmorphogenesis. Accomplishment of these goals will require the interaction of molecular epidemiologists, obstetricians, developmental toxicologists, molecular biologists and statisticians. The investigators for this proposal collectively represent these areas of expertise and have a history of working together in molecular epidemiology research and graduate teaching focused on the study of developmental defects. Interdisciplinary collaborations will be enhanced by participation of investigators in a seminar series on Molecular, Epidemiology of Developmental Defects. In addition, investigators will collaborate in establishing a tissue bank of human fetal tissues and in conducting a pilot project on the relationship between sequence variations in human HOX genes and developmental defects. The primary goal of this proposal is to provide a framework for interdisciplinary collaboration of investigators to foster research in the area of gene-environment interactions in the etiology of human developmental defects. The specific aims are to: (1) establish an interdisciplinary team of investigators with expertise in the areas of molecular epidemiology, obstetrics, developmental toxicology, environmental health sciences, molecular biology and biostatistics; (2) establish a bank of human fetal tissues consisting of chorionic villus samples and amniocytes and to develop a database to link these samples to clinical information on pregnancy outcome; (3)identify allelic frequencies of polymorphisms in selected HOX genes from human fetal DNA collected at different times in gestation from pregnancies with clinically normal outcomes; and (4) evaluate whether specific polymorphisms in these genes are associated with fetal lethality and/or dysmorphogenesis.